CN101550142A - Preparation method of Ulifloxacin optical isomer - Google Patents
Preparation method of Ulifloxacin optical isomer Download PDFInfo
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- CN101550142A CN101550142A CNA2008100272123A CN200810027212A CN101550142A CN 101550142 A CN101550142 A CN 101550142A CN A2008100272123 A CNA2008100272123 A CN A2008100272123A CN 200810027212 A CN200810027212 A CN 200810027212A CN 101550142 A CN101550142 A CN 101550142A
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- ulifloxacin
- dimethyl sulfoxide
- lisha star
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- optical isomer
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Abstract
The invention relates to a preparation method of a ulifloxacin optical isomer, in particular to a preparation method of a 6-fluorine-1-methyl-4-oxo-(1-piperazinyl)-1H and 4H-(1, 3) sulfur azetidine combined with (3, 2-a) quinoline-3-carboxylic acid optical isomer, which comprises the following steps: (+/-) ulifloxacin is taken to be dissolved in dimethyl sulfoxide, a dimethyl sulfoxide solution of D-tartaric acid is dropped into the dimethyl sulfoxide to obtain (S)-ulifloxacin-D-tartrate precipitation, the pH value of the (S)-ulifloxacin-D-tartrate is regulated by a NaOH solution in water after the (S)-ulifloxacin-D-tartrate is recrystallized so as to obtain precipitates, the precipitates are filtered and dried to obtain (S)-ulifloxacin, and the optical purity e.e. of the (S)-ulifloxacin is more than 95 percent. The preparation method of the ulifloxacin optical isomer is simple and convenient without special equipment requests and is beneficial to industrialized batch production, and an obtained optically active body has high purity.
Description
Technical field
The present invention relates to the preparation method in chemicals field, be specifically related to 6-fluoro-1-methyl-4-oxo-(1-piperazinyl)-1H, 4H-[1,3] the sulfur nitrogen heterocycle butane preparation method of [3,2-a] quinoline-3-carboxylic acid photoisomer also.
Background technology
The You Lisha star, international Ulifloxacin by name is a kind of anti-infective obvious results quinolones, its chemical name is (±) 6-fluoro-1-methyl-4-oxo-(1-piperazinyl)-1H, 4H-[1,3] sulfur nitrogen heterocycle butane also [3,2-a] quinoline-3-carboxylic acid, its structural formula is as shown in the formula 1:
The You Lisha star has broad-spectrum antibacterial action to gram positive organism and gram-negative bacteria, particularly bacteriums such as streptococcus aureus, streptococcus pneumoniae, enterococcus faecalis, the husky thunder bacterium of mucus, Pseudomonas aeruginosa is demonstrated the strong antibiotic effect.Experiment in vivo and vitro shows that all the You Lisha star is has a broad antifungal spectrum not only, and activity in vivo is strong, and than Ciprofloxacin and Ofloxacine USP 23 have good germicidal action and post antibiotic effect, cytotoxicity low, move the advantage such as few of dividing a word with a hyphen at the end of a line to central nervous system.
The You Lisha star contains a chirality carbon atom, it can produce the different optical isomer of opticity (S)-You Lisha star, structural formula is as shown in the formula 2 and (R)-You Lisha star, structural formula is as shown in the formula 3, (S)-antibacterial activity in vitro of You Lisha star be (R)-You Lisha star 3-10 doubly, be (±)-more than 2 times of You Lisha star.
[Chem.Pharm.Bull.43 (7) 1238-1240] such as Japanology person Jun Segawa utilizes high performance liquid chromatography, intermediate 6 with the You Lisha star, 7-two fluoro-1-methyl-4-oxo-1H, 4H-[1,3] the sulfur nitrogen heterocycle butane also [3,2-a] quinoline-3-carboxylic acid ethyl ester (be called for short P8) carry out chiral separation and separate, obtain (+)-P8 and (-)-P8, begin by (+)-P8 and (-)-P8 then, obtain (+)-and (-)-You Lisha star through two step chemosynthesis reactions respectively; And by monocrystalline x-ray analysis conclusive evidence (+)-and the C-1 absolute configuration of (-)-You Lisha star be respectively R and S.Obviously the above-mentioned method that is used to prepare ulifloxacin optical isomer exists equipment to have high input, and yields poorly, and only is suitable for academic research, and can't be applied to industrial-scale production.Therefore be necessary the method that preparation (S)-You Lisha star is produced in the new suitable industrialization of further research.
Summary of the invention
The method that the purpose of this invention is to provide a kind of suitable industrialization prepares the optics optically active isomer of You Lisha star.
To achieve the object of the present invention, the technical scheme that is adopted is: get (±) 6-fluoro-1-methyl-4-oxo-(1-piperazinyl)-1H, 4H-[1,3] the sulfur nitrogen heterocycle butane also [3,2-a] quinoline-3-carboxylic acid is dissolved in dimethyl sulfoxide (DMSO), stir and drip the tartaric dimethyl sulphoxide solution of D-down, stirred 20 hours for 20～40 ℃, obtain (S)-You Lisha star-D-tartrate precipitation in room temperature, this salt dimethyl sulfoxide (DMSO) is a solvent recrystallization, again crystallization is suspended in 30 times the water, stirs down and regulate the pH value to 7-8, get throw out with the NaOH aqueous solution, filter, filtration cakes torrefaction obtains (S)-You Lisha star of following structural formula 2, and optical purity: e.e. is greater than 95%; Or with (±) 6-fluoro-1-methyl-4-oxo-(1-piperazinyl)-1H, 4H-[1,3] the sulfur nitrogen heterocycle butane also [3,2-a] quinoline-3-carboxylic acid is dissolved in dimethyl sulfoxide (DMSO), stir and drip the tartaric dimethyl sulphoxide solution of L-down, stirred 20 hours for 20～40 ℃ in room temperature, obtain (R)-You Lisha star-L-tartrate precipitation, this salt recrystallization in dimethyl sulfoxide solvent, filter, filter cake is suspended in 30 times the water, stirs down and regulate the pH value to 7-8, get throw out with the NaOH aqueous solution, filter, filtration cakes torrefaction obtains (R)-You Lisha star of following structural formula 3, and optical purity: e.e. is greater than 95%.
Ulifloxacin optical isomer preparation technology provided by the present invention, method is easy, and no especial equipment requirements is beneficial to industrialized mass production, gained optically active body purity height.Following examples are further set forth technical scheme and beneficial effect.
Embodiment
The preparation of embodiment 1 (S)-You Lisha star
You Lisha star 105 grams of racemization are dissolved in the dimethyl sulfoxide (DMSO) of 1500mL, stir and drip the solution that 27 gram D-tartrate are dissolved in the 405mL dimethyl sulfoxide (DMSO) down, occur muddy and precipitation, stirred 20 hours under the room temperature, sedimentation and filtration, the gained solid is dry 86 grams that get under vacuum, with this solid recrystallization in dimethyl sulfoxide (DMSO), obtain left-handed You Lisha star-D-tartrate 37 grams, through ultimate analysis C49.08%, H5.06%, N9.50%, S7.44% (molecular composition: C
16H
16FN
3O
3S1/2C
4H
6O
6H
2O, calculated value C48.86%, H4.78, N9.50%, S7.25%); This salt is added entry become suspension, stir down and regulate the pH value to 7-8 with the 2%NaOH aqueous solution, the sedimentation and filtration drying obtains (S)-You Lisha star 24.5 grams, specific optical rotation
(c=0.15,0.1mol/LNaOH);
1H-NMR (DMSO-d
6) δ 2.11 (3H, d, j=6.2Hz), 2.87 (4H, m), 3.19 (4H, m), 6.40 (1H, q, j=6.2Hz), 6.89 (1H, d, j=7.4Hz), 7.79 (1H, d, j=13.9Hz), optical purity e.e.＞95%.
The preparation of embodiment 2 (R)-You Lisha star
You Lisha star 105 grams of racemization are dissolved among the DMSO of 1500mL, stir and drip the solution that 27 gram L-tartrate are dissolved in the 405mL dimethyl sulfoxide (DMSO) down, occur muddy and precipitation, stirred 20 hours under the room temperature, filter, the solid that obtains is dry 82 grams that get under vacuum, this solid recrystallization purifying in dimethyl sulfoxide (DMSO) is obtained dextrorotation You Lisha star-L-tartrate 34 grams, this salt is added entry become suspension, stir down and regulate the pH value to 7-8 with the 2%NaOH aqueous solution, filtration drying obtains (R)-You Lisha star 22 grams, specific optical rotation
(c=0.15,0.1mol/LNaOH), optical purity e.e.＞95%.
The test of embodiment 3 in-vitro antibacterials
Test method: adopt agar dilution to carry out the mensuration of minimal inhibitory concentration (MIC), antibacterials with different concns, join respectively in the quantitative nutrient agar, mixing, make the solid plate, make the concentration of contained antibacterials in each each plate differ two times, again the tested bacteria dibbling to the surface that adds the nutrient agar that contains antibacterials, cultivate, according to bacterial growth situation sentence read result.According to the stdn council of U.S. clinical labororatory standard, flat board placed on dead color, the no-reflection body surface judge test endpoint, with the lowest concentration of drug of asepsis growth is minimum inhibitory concentration (MIC) to this strain bacterium, and all the MIC with the Quality Control bacterial strain judges whether to meet the stdn council of U.S. clinical labororatory quality control standard in whole experiments.
If 2 above colony growths are arranged in containing on the agar plate that concentration is higher than the terminal point level, or long and the phenomenon of growing on the high concentration medicine agar plate then should be checked culture purity or revision test on the lower concentration medicine agar plate.
Test sample: Ciprofloxacin, levofloxacin, (±) You Lisha star are commercially available sample, medicine in contrast.(S)-You Lisha star, (R)-You Lisha star be by this patent embodiment and make by oneself.
The test bacterium is Klebsiella Pneumoniae (bacterial strain number for CMCC 46114-8), Pseudomonas aeruginosa (bacterial strain number be CMCC10104, ATCC 27853), escherichia coli (bacterial strain number be ATCC8739, CMCC44102, ATCC25922), streptococcus aureus (bacterial strain number be CMCC 26003, ATCC6538, ATCC25925), separate in the phlegm that other experimental bacteria pearls are hospital clinical acute bacterial respiratory tract or urinary tract infection patient, throat swab or the urine, and the bacterium of identifying through hospital.
With (S)-You Lisha star, (R)-You Lisha magnitude trial-product by labelled amount proofread and correct the back precision take by weighing be equivalent to 96mg You Lisha star be subjected to the reagent thing, be settled to 50ml with the aseptic distillation water dissolution; Levofloxacin hydrochloride injection liquid, ciprofloxacin lactate sodium chloride injection all are diluted to the solution that concentration is 1920 μ g/ml with sterile purified water.The in-vitro antibacterial experimental result sees Table 1.
Table 1, in-vitro antibacterial test MIC (μ g/ml)
Conclusion: the result shows, (S)-anti-microbial activity of You Lisha star is 3～10 times of (R)-You Lisha star, (S)-anti-microbial activity of You Lisha star be 2 times of (±)-You Lisha star or more than.
Claims (1)
1, a kind of preparation method of ulifloxacin optical isomer, it is characterized in that: get (±) 6-fluoro-1-methyl-4-oxo-(1-piperazinyl)-1H, 4H-[1,3] the sulfur nitrogen heterocycle butane also [3,2-a] quinoline-3-carboxylic acid is dissolved in dimethyl sulfoxide (DMSO), stir and drip the tartaric dimethyl sulphoxide solution of D-down, stirred 20 hours for 20～40 ℃ in room temperature, obtain (S)-You Lisha star-D-tartrate precipitation, this salt dimethyl sulfoxide (DMSO) is a solvent recrystallization, again crystallization is suspended in 30 times the water, stir down and regulate the pH value to 7-8 with the NaOH aqueous solution, get throw out, filter, filtration cakes torrefaction, obtain (S)-You Lisha star of following structural formula (2), or with (±) 6-fluoro-1-methyl-4-oxo-(1-piperazinyl)-1H, 4H-[1,3] the sulfur nitrogen heterocycle butane also [3,2-a] quinoline-3-carboxylic acid is dissolved in dimethyl sulfoxide (DMSO), stir and drip the tartaric dimethyl sulphoxide solution of L-down, stirred 20 hours for 20～40 ℃, obtain (R)-You Lisha star-L-tartrate precipitation in room temperature, this salt recrystallization in dimethyl sulfoxide solvent, filter, filter cake is suspended in 30 times the water, stir down with NaOH aqueous solution adjusting pH value to 7-8, get throw out, filter, filtration cakes torrefaction obtains (R)-You Lisha star of following structural formula (3).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100272123A CN101550142B (en) | 2008-04-03 | 2008-04-03 | Preparation method of ulifloxacin optical isomer |
| PCT/CN2009/071137 WO2009121304A1 (en) | 2008-04-03 | 2009-04-02 | Preparation of ulifloxacin optical isomer |
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| CN2008100272123A CN101550142B (en) | 2008-04-03 | 2008-04-03 | Preparation method of ulifloxacin optical isomer |
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| CN101550142A true CN101550142A (en) | 2009-10-07 |
| CN101550142B CN101550142B (en) | 2011-04-27 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011085606A1 (en) | 2010-01-13 | 2011-07-21 | 广州医药工业研究院 | Optically active compound of prulifloxacin for treating infection and preparation method thereof |
| CN102198134A (en) * | 2010-03-22 | 2011-09-28 | 北京联木医药技术发展有限公司 | Use of new stable Ulifloxacin hydrochloride in preparation of anti-infection medicine |
| CN102424689A (en) * | 2011-12-31 | 2012-04-25 | 广州医药工业研究院 | Levo ulifloxacin mesylate crystal as well as preparation method and application thereof |
| CN102424688A (en) * | 2011-12-31 | 2012-04-25 | 广州医药工业研究院 | Levoulifloxacin mesylate crystal, its preparation method and application |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2536678B2 (en) * | 1989-11-17 | 1996-09-18 | 日本新薬株式会社 | Optically active quinolinecarboxylic acid derivative |
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2008
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011085606A1 (en) | 2010-01-13 | 2011-07-21 | 广州医药工业研究院 | Optically active compound of prulifloxacin for treating infection and preparation method thereof |
| CN102198134A (en) * | 2010-03-22 | 2011-09-28 | 北京联木医药技术发展有限公司 | Use of new stable Ulifloxacin hydrochloride in preparation of anti-infection medicine |
| CN102198134B (en) * | 2010-03-22 | 2013-06-26 | 北京联木医药技术发展有限公司 | Use of new stable Ulifloxacin hydrochloride in preparation of anti-infection medicine |
| CN102424689A (en) * | 2011-12-31 | 2012-04-25 | 广州医药工业研究院 | Levo ulifloxacin mesylate crystal as well as preparation method and application thereof |
| CN102424688A (en) * | 2011-12-31 | 2012-04-25 | 广州医药工业研究院 | Levoulifloxacin mesylate crystal, its preparation method and application |
| CN102424689B (en) * | 2011-12-31 | 2014-05-28 | 广州医药工业研究院 | Levo ulifloxacin mesylate crystal as well as preparation method and application thereof |
| CN102424688B (en) * | 2011-12-31 | 2014-08-20 | 广州医药工业研究院 | Levoulifloxacin mesylate crystal, its preparation method and application |
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| Publication number | Publication date |
|---|---|
| CN101550142B (en) | 2011-04-27 |
| WO2009121304A1 (en) | 2009-10-08 |
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Correction item: Patentee Correct: Guangzhou Pharmaceutical Industry Research Institute|510240. No. 134, Jiangnan Road, Guangzhou, Guangdong, Haizhuqu District|Baiyunshan Pharmaceutical General Factory, Baiyunshan Pharmaceutical Co., Ltd, G False: Guangzhou Pharmaceutical Industry Research Institute|510240. No. 134, Jiangnan Road, Guangzhou, Guangdong, Haizhuqu District|Baiyunshan Pharmaceutical General Factory, Baiyunshan Pharmaceutical Co., Ltd, G Number: 17 Volume: 27 |
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Address after: 510240 Haizhuqu District Jiangnan Road, Guangdong, No. 134, No. Patentee after: GUANGZHOU GENERAL PHARMACEUTICAL RESEARCH INSTITUTE Co.,Ltd. Patentee after: GUANGZHOU BAIYUNSHAN PHARMACEUTICAL HOLDINGS Co.,Ltd. BAIYUNSHAN PHARMACEUTICAL GENERAL FACTORY Address before: 510240 Haizhuqu District Jiangnan Road, Guangdong, No. 134, No. Patentee before: Guangzhou General Pharmaceutical Research Institute Patentee before: GUANGZHOU BAIYUNSHAN PHARMACEUTICAL HOLDINGS Co.,Ltd. BAIYUNSHAN PHARMACEUTICAL GENERAL FACTORY Address after: 510240 Haizhuqu District Jiangnan Road, Guangdong, No. 134, No. Patentee after: GUANGZHOU GENERAL PHARMACEUTICAL Research Institute Patentee after: GUANGZHOU BAIYUNSHAN PHARMACEUTICAL HOLDINGS Co.,Ltd. BAIYUNSHAN PHARMACEUTICAL GENERAL FACTORY Address before: 510240 Haizhuqu District Jiangnan Road, Guangdong, No. 134, No. Patentee before: GUANGZHOU INSTITUTE OF PHARMACEUTICAL INDUSTRY Patentee before: GUANGZHOU BAIYUNSHAN PHARMACEUTICAL Co.,Ltd. GUANGZHOU BAIYUNSHAN PHARMACEUTICAL FACTORY |